Discovering cell reactions through the role of bitter taste receptors in cancer treatment

Researchers consider the benefits of bitter compounds as a potential therapeutic

Cancer is a global problem

Cancer is a disease that is far-reaching, impacting millions of lives, every day. According to the World Health Organization, cancer is a leading cause of death worldwide—in fact, it was the cause of one in six deaths in 2020. Although cancer is a global problem, access to therapies, which are often invasive and costly, varies significantly around the world with treatment availability at more than 90% in high-income countries, but less than 15% in low-income countries. While access to these therapeutics is part of the problem, variety in the types of treatments available could also provide relief to millions. And that’s where science is heading.

Research on bitter taste receptors

Dr. Derek McMahon, a former postdoctoral fellow at the University of Pennsylvania, focused his research toward this goal, by investigating the role of bitter taste receptors in the human airway. Dr. McMahon and his team found that these taste receptors, initially identified on the tongue, are also expressed in both the human airway and in head and neck squamous cell carcinoma (HNSCC). Interestingly, stimulation of these receptors with bitter compounds can activate an intracellular response that has a therapeutic potential for this type of cancer.

Bitter taste receptors in the human airway

Every inhalation is an opportunity for invading pathogens to enter your airway passages. As a defense, the human airway is lined with cells that act as “sentinels”; these cells are specialized in monitoring bacterial growth. Most of these cells are multi-ciliated airway epithelial cells, which contain special, finger-like structures known as motile cilia. These cilia coordinate their rhythmic movements to transport mucus out of the airway. Interestingly, bitter taste receptors are localized to motile cilia. These taste receptors function to detect bacterial products (such as quorum-sensing molecules) and signal the production of nitric oxide, which directly kills bacteria. This signaling pathway also causes the motile cilia to beat faster, thus increasing the rate of mucus clearance from the airway. In this manner, bacteria ensnared in a web of mucus are killed and removed from the airway.

Diseases causing loss of protective layer

Unfortunately, several diseases, such as COPD, cystic fibrosis, chronic rhinosinusitis or severe asthma, and viral infections from SARS-CoV-2 to influenza viruses, lead to a remodeling of the airway epithelium. In a diseased patient, there is a dysfunction of or loss of motile cilia and/or squamous cell metaplasia. This results in a loss of the protective layer of multi-ciliated epithelial cells. So that raised the question for Dr. McMahon: “What happens to bitter taste receptor expression, localization, and function in a disease state when multi-ciliated cells aren’t present?”

Using basal airway epithelial cells, which lack motile cilia, as a disease model, Dr. McMahon “found that … some of the bitter taste receptors that would normally be localized to the cilia on the multi-ciliated cells, are  instead localized to the nucleus of basal epithelial cells. Bitter compounds [typically hydrophobic] can permeate into these cells, activate the bitter taste receptors and increase nitric oxide production, which is a great innate immune response, but they also signal through nuclear and mitochondrial calcium pathways, which leads to apoptosis.”

Apoptosis, or the process of programmed cell death used to rid the body of cells damaged beyond repair, is an important piece of the equation—especially when considering how bitter compounds have the potential to act as therapies for diseases, including cancer. Given that the introduction of bitter compounds eventually leads to apoptosis, they could be used to target HNSCC.

Detection of bitter taste receptor protein receptors

A challenging aspect of this research lies in detecting the protein expression of these taste receptors. There are a few techniques, such as Western blot and immuno-fluorescent microscopy, that allow for the direct observation of protein expression, but antibodies must be raised against the protein of interest and further validated for these methods to be successful.

Since many of the taste receptors being studied do not have commercially available antibodies, Dr. McMahon and his team needed to find another way to detect protein expression. The team found that they could bypass the need for antibodies by instead detecting RNA expression. Within the nucleus of the cell, DNA is transcribed to RNA which is eventually exported from the nucleus as messenger RNA (mRNA). This mRNA is used as a precursor to protein synthesis in the cytoplasm of the cell. By detecting the presence of taste receptor mRNA, they could gain insights into which taste receptor proteins may be expressed.

Techniques for detecting protein expression

“To detect the RNA expression, we’ve been using Applied Biosystems™ technologies TaqMan™ probes for qPCR,” Dr. McMahon said. “We’ve found that they are extremely robust and very specific in differentiating between the 25 different bitter taste receptors in humans.” These findings, combined that with their observations that airway cells can detect bitter compounds, supported their hypothesis that bitter taste receptor proteins must be expressed. Additionally, they have found that some of these taste receptors are expressed at a higher level in HNSCC cells and therefore may be more susceptible to apoptosis than healthy, non-cancerous cells.

Dr. McMahon explained that, ideally, drugs already on the market could be repurposed since many of them already contain bitter compounds. Quinine, a bitter compound that is most known from tonic water, is a great example—it’s an anti-malarial treatment that activates nine different bitter taste receptors and induces apoptosis in some cells.

“I’m hoping that we can use bitter compounds to activate the innate immune system to either combat infections or come up with targeted therapies for some types of cancer,” Dr. McMahon said. “Taste receptors are found throughout the human body, and there are 25 bitter taste receptors, so there’s plenty of research ahead of us.”

Learn more about how Applied Biosystems solutions are enabling cancer research at thermofisher.com/abcancerresearch.

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